Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3Kγ-dependent fluid-phase pinocytosis of native LDL

Anzinger, Joshua J.; Chang, Joan; Xu, Qing; Barthwal, Manoj Kumar; Bohnacker, Thomas; Wymann, Matthias P.; Kruth, Howard S.

doi:10.1194/jlr.m018887

Cited by 38 publications

(38 citation statements)

References 42 publications

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“…Previous studies on the importance of macropinocytosis were restricted to LDL [5, 6, 24, 25] but we found that this also extends to modified LDL [7]. Overall, our studies demonstrate that PI3K is important for both receptor-mediated uptake processes and macropinocytosis, and confirms links that were identified in some previous studies [5, 6, 24–26]. …”

Section: Discussionsupporting

confidence: 90%

The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

Michael

Davies

Laubertová

et al. 2015

Lipids

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The transformation of macrophages into lipid-loaded foam cells is a critical early event in the pathogenesis of atherosclerosis. Both receptor-mediated uptake of modified LDL, mediated primarily by scavenger receptors-A (SR-A) and CD36 along with other proteins such as lipoprotein lipase (LPL), and macropinocytosis contribute to macrophage foam cell formation. The signaling pathways that are involved in the control of foam cell formation are not fully understood. In this study, we have investigated the role of phosphoinositide 3-kinase (PI3K) in relation to foam cell formation in human macrophages. The pan PI3K inhibitor LY294002 attenuated the uptake of modified LDL and macropinocytosis, as measured by Lucifer Yellow uptake, by human macrophages. In addition, the expression of SR-A, CD36 and LPL was attenuated by LY294002. The use of isoform-selective PI3K inhibitors showed that PI3K-β, -γ and -δ were all required for the expression of SR-A and CD36 whereas only PI3K-γ was necessary in the case of LPL. These studies reveal a pivotal role of PI3K in the control of macrophage foam cell formation and provide further evidence for their potential as therapeutic target against atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s11745-015-3993-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 90%

The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

Michael

Davies

Laubertová

et al. 2015

Lipids

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“…This PI3Kg-dependant infiltration can be initiated by chemokine or matrix extracellular degradation product such as elastin peptides which activate a elastin complex receptor expressed at the surface of immune cells able to recruit PI3Kg . Moreover, the work of Anzinger et al demonstrated that GMeCSFedifferentiated murine macrophages become foam cells by fluid-phase pinocytosis of LDL and identified PI3Kg as contributing to this process (Anzinger et al, 2012). Together these results, reinforced further by others , prove that targeting the PI3Kg isoform in this pathological context is of great interest.…”

Section: C2-a Endothelial Cellmentioning

confidence: 82%

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

Lupieri

Smirnova

Malet

et al. 2015

Advances in Biological Regulation

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“…Bone marrow isolation was performed as described previously 12. The bone marrow cells were differentiated into BMDMs with macrophage colony-stimulating factor (M-CSF) (Peprotech, Rocky Hill, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer

Liu¹,

Tu²,

Wang³

et al. 2016

OTT

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BackgroundAlthough anti-angiogenic therapy is widely applied clinically, its efficacy has been less than expected. Screening for regulatory factors and sensitive indicators to define the effectiveness of these drugs is required. Through a retrospective study of clinical data, we found that patients with a higher peripheral monocyte-to-lymphocyte ratio (MLR) obtained less benefit from recombinant human endostatin (rhES, Endostar®), an anti-angiogenic drug, in lung cancer. Because MLR is positively correlated with macrophage count in tumors, this result suggests that macrophages may influence the effectiveness of rhES therapy in lung cancer.MethodsClinical data from 72 lung cancer patients treated with rhES were collected. Animal study, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, Western blot analysis, and transwell migration assays were carried on Lewis lung carcinoma (LLC) cells, bone marrow-derived macrophages, macrophage cell line RAW264.7, and ANA-1 cells.ResultsClinical data showed that compared with the baseline MLR before rhES treatment, patients with progressive disease had higher MLRs than those of patients with partial response. Experimental results showed that more macrophages were recruited in the LLC tumors after rhES treatment and the majority of them displayed an M2-like phenotype. rhES aggravated hypoxia and the inflammatory response in the tumor microenvironment. Hypoxia promoted the expression of CCL2 by endothelial and fibroblast cells, which could induce macrophages recruitment, and increased levels of inflammatory cytokines (interleukin-4 [IL-4], IL-6, and IL-10) skewed macrophage polarization toward the M2-like phenotype. Hypoxia or inflammation cytokine-treated macrophages enhanced the progression of LLC in vitro and in vivo.ConclusionWe found rhES could aggravate hypoxia and the inflammatory response in the tumor microenvironment. These changes were favorable for macrophage accumulation, and skewed their polarization toward the M2-like phenotype which could help LLC to escape from the anti-angiogenic therapy. Thus, these data indicate the accumulation of macrophages in the tumor microenvironment may adversely affect the efficacy of rhES on lung cancer.

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Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3Kγ-dependent fluid-phase pinocytosis of native LDL

Cited by 38 publications

References 42 publications

The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

PI3K signaling in arterial diseases: Non redundant functions of the PI3K isoforms

The accumulation of macrophages attenuates the effect of recombinant human endostatin on lung cancer

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